P47973 · TTP_RAT
- ProteinmRNA decay activator protein ZFP36
- GeneZfp36
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids320 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Zinc-finger RNA-binding protein that destabilizes numerous cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:27193233).
Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA (By similarity).
Binds to 3'-UTR ARE of numerous mRNAs (PubMed:27193233).
Binds also to ARE of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (By similarity).
Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA (By similarity).
Binds to 3'-UTR ARE of numerous mRNAs (PubMed:27193233).
Binds also to ARE of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (By similarity).
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended namemRNA decay activator protein ZFP36
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Rattus
Accessions
- Primary accessionP47973
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Shuttles between nucleus and cytoplasm in a CRM1-dependent manner (PubMed:12054509).
Localized predominantly in the cytoplasm in a p38 MAPK- and YWHAB-dependent manner. Colocalizes with SH3KBP1 and MAP3K4 in the cytoplasm. Component of cytoplasmic stress granules (SGs). Localizes to cytoplasmic stress granules upon energy starvation. Localizes in processing bodies (PBs). Excluded from stress granules in a phosphorylation MAPKAPK2-dependent manner. Shuttles in and out of both cytoplasmic P-body and SGs (By similarity).
Localized predominantly in the cytoplasm in a p38 MAPK- and YWHAB-dependent manner. Colocalizes with SH3KBP1 and MAP3K4 in the cytoplasm. Component of cytoplasmic stress granules (SGs). Localizes to cytoplasmic stress granules upon energy starvation. Localizes in processing bodies (PBs). Excluded from stress granules in a phosphorylation MAPKAPK2-dependent manner. Shuttles in and out of both cytoplasmic P-body and SGs (By similarity).
Keywords
- Cellular component
Phenotypes & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 3 | Inhibits nucleus export. | ||||
Sequence: L → A | ||||||
Mutagenesis | 10 | Inhibits nucleus export. | ||||
Sequence: L → A |
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000089165 | 1-320 | mRNA decay activator protein ZFP36 | |||
Sequence: MDLSAIYESLMSMSHDLSPDHGGTESSGGLWNINSSDSIPSGVTSRLTGRSTSLVEGRSCSWVPPPPGFAPLAPRPGPELSPSPTSPTATPTTSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLALPGQPHVLRQSISFSGLPSGRRTSPPPPGFSGPSLSSCSFSPSSSPPPPGDLPLSPSAFSAAPGTPVSRRDPTPACCPSCRRSTTPSTIWGPLGGLARSPSAHSLGSDPDDYASSGSSLGGSDSPVFEAGVFGPPQPPAPPRRLPIFNRISVSE | ||||||
Modified residue | 53 | Phosphoserine; by MAPKAPK2 | ||||
Sequence: S | ||||||
Modified residue | 59 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 81 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 83 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 85 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 86 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 179 | Phosphoserine; by MAPKAPK2 | ||||
Sequence: S | ||||||
Modified residue | 190 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 211 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 221 | Phosphoserine; by MAPK1; in vitro | ||||
Sequence: S | ||||||
Modified residue | 251 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 270 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 290 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 317 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. Phosphorylated by MAPKAPK2 at Ser-53 and Ser-179; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. Phosphorylated at Ser-59 and Ser-86; these phosphorylations increase in a SH3KBP1-dependent manner. Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner. Phosphorylation at Ser-53 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. Dephosphorylated by serine/threonine phosphatase 2A at Ser-179.
Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes. Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates with the RNA exosome complex. Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner. Interacts with AGO2 and AGO4. Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation. Interacts (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts with EDC3. Interacts (via N-terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. Interacts with KHSRP; this interaction increases upon cytokine-induced treatment. Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85. Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation. Interacts with NCL. Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation. Interacts with PABPC1; this interaction occurs in a RNA-dependent manner. Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) with PKM. Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay. Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner. Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-59 and Ser-86 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay. Interacts with XRN1. Interacts (via C-terminus and Ser-179 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-179 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs. Interacts (via phosphorylated form) with YWHAE. Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner. Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner. Does not interact with SH3KBP1. Interacts (via P-P-P-P-G repeats) with GIGYF2; the interaction is direct (By similarity).
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, compositional bias, repeat, zinc finger.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-15 | Necessary for nuclear export | ||||
Sequence: MDLSAIYESLMSMSH | ||||||
Region | 1-93 | Necessary and sufficient for the association with mRNA decay enzymes and mRNA decay activation | ||||
Sequence: MDLSAIYESLMSMSHDLSPDHGGTESSGGLWNINSSDSIPSGVTSRLTGRSTSLVEGRSCSWVPPPPGFAPLAPRPGPELSPSPTSPTATPTT | ||||||
Region | 1-167 | Necessary for localization of ARE-containing mRNAs to processing bodies (PBs) | ||||
Sequence: MDLSAIYESLMSMSHDLSPDHGGTESSGGLWNINSSDSIPSGVTSRLTGRSTSLVEGRSCSWVPPPPGFAPLAPRPGPELSPSPTSPTATPTTSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLAL | ||||||
Region | 17-50 | Disordered | ||||
Sequence: LSPDHGGTESSGGLWNINSSDSIPSGVTSRLTGR | ||||||
Compositional bias | 19-50 | Polar residues | ||||
Sequence: PDHGGTESSGGLWNINSSDSIPSGVTSRLTGR | ||||||
Repeat | 64-68 | P-P-P-P-G | ||||
Sequence: PPPPG | ||||||
Compositional bias | 66-85 | Pro residues | ||||
Sequence: PPGFAPLAPRPGPELSPSPT | ||||||
Region | 66-95 | Disordered | ||||
Sequence: PPGFAPLAPRPGPELSPSPTSPTATPTTSS | ||||||
Region | 88-161 | Necessary for nuclear localization | ||||
Sequence: TATPTTSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNP | ||||||
Region | 90-166 | Necessary for RNA-binding | ||||
Sequence: TPTTSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLA | ||||||
Region | 93-320 | Necessary for localization of ARE-containing mRNAs to processing bodies (PBs) | ||||
Sequence: TSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLALPGQPHVLRQSISFSGLPSGRRTSPPPPGFSGPSLSSCSFSPSSSPPPPGDLPLSPSAFSAAPGTPVSRRDPTPACCPSCRRSTTPSTIWGPLGGLARSPSAHSLGSDPDDYASSGSSLGGSDSPVFEAGVFGPPQPPAPPRRLPIFNRISVSE | ||||||
Zinc finger | 96-124 | C3H1-type 1 | ||||
Sequence: RYKTELCRTYSESGRCRYGAKCQFAHGPG | ||||||
Region | 96-187 | Necessary for interaction with PABPN1 | ||||
Sequence: RYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLALPGQPHVLRQSISFSGLPSGR | ||||||
Zinc finger | 134-162 | C3H1-type 2 | ||||
Sequence: KYKTELCHKFYLQGRCPYGSRCHFIHNPT | ||||||
Region | 167-320 | Necessary for mRNA decay activation | ||||
Sequence: LPGQPHVLRQSISFSGLPSGRRTSPPPPGFSGPSLSSCSFSPSSSPPPPGDLPLSPSAFSAAPGTPVSRRDPTPACCPSCRRSTTPSTIWGPLGGLARSPSAHSLGSDPDDYASSGSSLGGSDSPVFEAGVFGPPQPPAPPRRLPIFNRISVSE | ||||||
Region | 180-310 | Disordered | ||||
Sequence: FSGLPSGRRTSPPPPGFSGPSLSSCSFSPSSSPPPPGDLPLSPSAFSAAPGTPVSRRDPTPACCPSCRRSTTPSTIWGPLGGLARSPSAHSLGSDPDDYASSGSSLGGSDSPVFEAGVFGPPQPPAPPRRL | ||||||
Repeat | 191-195 | P-P-P-P-G | ||||
Sequence: PPPPG | ||||||
Repeat | 212-216 | P-P-P-P-G | ||||
Sequence: PPPPG | ||||||
Compositional bias | 274-288 | Polar residues | ||||
Sequence: DPDDYASSGSSLGGS | ||||||
Region | 306-320 | Interaction with CNOT1 | ||||
Sequence: PPRRLPIFNRISVSE |
Domain
The C3H1-type zinc finger domains are necessary for ARE-binding activity.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length320
- Mass (Da)33,654
- Last updated1996-10-01 v1
- ChecksumCFC597F3C7E5CA76
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
G3V8K6 | G3V8K6_RAT | Zfp36 | 326 |
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 19-50 | Polar residues | ||||
Sequence: PDHGGTESSGGLWNINSSDSIPSGVTSRLTGR | ||||||
Compositional bias | 66-85 | Pro residues | ||||
Sequence: PPGFAPLAPRPGPELSPSPT | ||||||
Compositional bias | 274-288 | Polar residues | ||||
Sequence: DPDDYASSGSSLGGS |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
X63369 EMBL· GenBank· DDBJ | CAA44970.1 EMBL· GenBank· DDBJ | mRNA | ||
AB025017 EMBL· GenBank· DDBJ | BAB12432.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC060308 EMBL· GenBank· DDBJ | AAH60308.1 EMBL· GenBank· DDBJ | mRNA |